Diet has strong effects on aging and diseases such as cancer

Over-eatingCalorie Restriction (CR)

How does diet regulate organ regeneration and cancer?

Organism) Lifespan)increase)with)caloric)restric4on)(CR))Yeast& 3(fold&Worms& 2(3&fold&Flies& 2(fold&Mice& 30(50%&Monkeys& 10%&or&no&effect&Humans) Not)studied)

Fontana L et al. Science. 2010 Apr 16;328(5976):321-6 Mattison, J. A. et al. Nature 489, 318–321 (2012) Coleman RJ et al. Nat Commun. 2014 Apr 1;5:3557

Extending life span with caloric restriction - from yeast to humans

Lgr5+ stem cells at the base of crypts maintain the intestinal epithelium

Clevers,Nature2007;Lewis,NatureReviewsGene2cs2006

Lgr5+

Lgr5‐Lgr5‐

Lgr5‐Lgr5‐

GFPhi

GFPlow

Lgr5+

stem cell

Paneth cell

niche

T Sato et al. Nature 000, 1-4 (2009) doi:10.1038/nature07935

Single Lgr5+ cells generate crypt–villus structures.

Sato et al 2009 Yilmaz et al 2012

Engineering “mini-intestines” in culture

Test effects of dietary components in 3-D miniature organs

cADPR

Calorie restriction

mTORC1

differentiation

self-renewal

Effect of a low calorie state on stem cells

Can CR or its mimetics enhance intestinal regeneration in patients?

Enema of cADPR heals intestinal injury

Smoking

Overweight and obesity

Lack of exercise

Diet

Occupation

Viruses

Family history

Alcohol

UV and ionizing radiation

Prescription Drugs

Reproductive factors

Pollution

adapted from Colditz et al., Science Translation Medicine, 2012

Smoking

Overweight and obesity

Obesity is a diet-modifiable cause of cancer

HFD boosts stem cell function

Control

HFD

**

*

*

**

*

0

0.2

0.4

0.6

0.8

Control' HFD'

Org

anoi

d pe

r cry

pt

'

*

Palmitic acid is an abundant component of the HFD

Palmitic Acid

PAVehicle

organoids from crypts

Vehicle PA

2

1

0

3

4 *%

GFP

hi p

ositi

ve s

tem

cel

ls

Org

anoi

d pe

r ste

m c

ell

Vehicle PA

Vehicle

PA

Side

Sca

tter A

rea

EGFP

1.5 ± 0.3%

3.3 ± 0.7%**0

0.06

0.04

0.02

0.10

0.08

**0.12

Ex vivo exposure of “mini-intestines” to Palmitic Acid boosts stem cell numbers and function

Similar results observed with oleic acid and other lipids

If stem cell activity increases, HFD should raise tumor incidence

mutation

If stem cell activity increases, HFD should raise tumor incidence

Inci

denc

e

0.8

0.6

0.4

0.2

0.7

0.5

0.3

0.1

Number of intestinal carcinoma per mouse

Aged Aged+HFD

Potential contributor to obesity-induced increase in cancer incidence?